PS15. STEM CELL TRANSPLANTATION IN HEMOGLOBINOPATHIES
M. AKIF YESILIPEK Akdeniz University School of Medicine Department of Pediatric Hematology-Oncology Antalya-Turkey; e-mail: yesilipek@akdeniz.edu.tr
*Corresponding Author:
page: 23

Abstract

Beta thalassemia and sickle cell disease (SCD) are the most common genetic diseases worldwide. Insufficient β-globin production leads to increased accumulation of α-globin chains, ineffective erythropoiesis and reduced red cell survival in beta thalassemia patients. Lifelong red cell transfusion and chelation therapy have improved survival of patients but can not eliminate disease and treatment-related complications such as endocrine dysfunctions, progressive liver fibrosis, cardiac diseases and post-transfusional viral infections resulting in poor quality of life and increased mortality. Some drugs like hydroxyurea offers beneficial effect for patients with SCD but can not prevent end-organ damage and modify the natural course of the disease. Allogeneic hematopoetic stem cell transplantation (HSCT) is considered the only curative treatment approach for the hemoglobinopathies.

Since the first report of bone marrow transplantation (BMT) in 1982, more than 1500 patients worldwide have received hematopoetic stem cell transplantation (HSCT) for beta thalassemia major. Pesaro group, the largest single institution experience, reported that three risk factors such as the presence of hepatomegaly more than 2 cm, liver fibrosis or irregularly iron chelation therapy  in pre-transplantation period have been shown to correlate with outcome of the patients. In Pesaro series, Class I patients who had no risk factor have shown the best results with thalassemia-free survival of 90%. Class II patients had one or two of these risk factors and showed 84% diseases free survival (DFS). However, among poor-risk patients with iron overload and liver disease from inadequate chelation, DFS was approximately 50%.  These data strongly suggested that the optimal timing of HSCT is in the very young child who has a HLA-identical sibling donor. New preparative regimens have been suggested for high risk and adult patients to reduce the toxicity and mortality. In our department 60 patients underwent HSCT have thalassemia free survival and over all survival as 84% and 91%, respectively.

Although the first BMT for SCD was carried out in 1984, lower number of patients received transplantation than undertaken during the same period for thalassemia. In all these studies, the main indications for transplantation were vasoocclusive complications such as stroke, recurrent episodes of acute chest syndrome, and/or painful crisis. Overall, 91% of the patients survived and 82% survived free of sickle cell anemia after HSCT. 

Application of HSCT is limited by donor availability. Approximately 70% of the patients with β-thalassemia lack a matched related donor. Although successful results were reported the use of mismatched related or matched unrelated donors is associated with a higher risk for graft rejection and GVHD in beta thalassemia and not generally recommended. Recently, cord blood transplantation (CBT) in patients with either  beta-thalassemia or SCD has been reported with lower GVHD. However, graft failure and recurrence of disease are seen as major problem for CBT in hemoglobinopathies.

Mixed hematopoetic chimerism (MC) and iron overload should be investigated closely in post-transplant period in hemoglobinopathy patients. Presence of MC is not unusual event after HSCT. It is well known that graft rejection risk is higher in thalassemia patients with early MC who have more than 25% residual host cell. These patients may benefit from donor lymphocyte infusion in order to reduce the risk of rejection. However, some of patients who become ex-thalassemic after HSCT show persistence of high proportion of host type cells with only a small proportion of donor cells for years.  In fact, 20% of donor marrow cells are sufficient to produce enough beta-globin synthesis with stable normal levels of hemoglobin in the peripheral blood. A similar observation was made for SCD with 10% donor cells but remained transfusion independent and no clinical symptoms.  

Although allogeneic HSCT can cure the hematological defect the vast majority of these patients still carry the clinical complications such as hepatic, cardiac diseases and endocrine dysfunctions due to iron overload. It has been reported that iron stores remain elevated after transplantation in patients who had advanced stages of disease. In these patients, regular phlebotomy and iron chelation therapy, starting 1-2 years after HSCT, have been found to be safe and effective to remove excess iron and prevent the complications.

In conclusion, HSCT can offer cure for hemoglobinopathy patients. HSCT should be performed in early childhood before iron overload and disease related complications. It needs multicenter trials to identify the ideal conditioning to reduce graft rejection rate and to improve DFS especially for high risk patients. Treatment of iron overload after a successful HSCT is necessary to improve multiorgan dysfunctions. 




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